Infrared spectroscopy imaging of libraries

ABSTRACT

Methods and apparatus for screening diverse arrays of materials using infrared imaging techniques are provided. Typically, each of the individual materials on the array will be screened or interrogated for the same material characteristic. Once screened, the individual materials may be ranked or otherwise compared relative to each other with respect to the material characteristic under investigation. According to one aspect, infrared imaging techniques are used to identify the active sites within an array of compounds by monitoring the temperature change resulting from a reaction. This same technique can also be used to quantify the stability of each new material within an array of compounds. According to another aspect, identification and characterization of condensed phase products is achieved, wherein library elements are activated by a heat source serially, or in parallel. According to another aspect, a Fourier transform infrared spectrometer is used to rapidly characterize a large number of chemical reactions contained within a combinatorial library.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of commonly assignedU.S. patent application Ser. No. 08/898,715, filed Jul. 22, 1997, and acontinuation-in-part of commonly assigned, co-pending U.S. ProvisionalApplications Serial No. 60/050,949, filed Jun. 13, 1997; No. 60/028,106,filed Oct. 9, 1996; No. 60/029,255, filed Oct. 25, 1996; No. 60/035,366,filed Jan. 10, 1997; No. 60/048,987, filed Jun. 9, 1997; No. 60/028,105,filed Oct. 9, 1996; and No. 60/035,202, filed Jan. 10, 1997; thecomplete disclosures of which are incorporated herein by reference forall purposes.

[0002] This application is also related to commonly assigned, co-pendingU.S. patent applications Ser. Nos. 08/327,513, filed Oct. 18, 1994, Ser.No. 08/438,043, filed May 8, 1995, and Ser. No. 08/841,423, filed Apr.22, 1997; commonly assigned U.S. Provisional Application Serial No.60/016,102, filed Jul. 23, 1996; and PCT Application No. WO 95/13278,filed Oct. 18, 1995; the complete disclosures of which are incorporatedherein by reference for all purposes.

FIELD OF THE INVENTION

[0003] The present invention generally relates to methods and apparatusfor rapidly screening an array of diverse materials which have beencreated at known locations on a single substrate surface, and inparticular to the combinatorial synthesis and characterization oflibraries of diverse materials using IR imaging and spectroscopytechniques.

BACKGROUND OF THE INVENTION

[0004] The discovery of new materials with novel chemical and physicalproperties often leads to the development of new and usefultechnologies. Currently, there is a tremendous amount of activity in thediscovery and optimization of materials, such as superconductors,zeolites, magnetic materials, phosphors, catalysts, thermoelectricmaterials, high and low dielectric materials and the like.Unfortunately, even though the chemistry of extended solids has beenextensively explored, few general principles have emerged that allow oneto predict with certainty the composition, structure and reactionpathways for the synthesis of such solid state compounds.

[0005] The preparation of new materials with novel chemical and physicalproperties is at best happenstance with our current level ofunderstanding. Consequently, the discovery of new materials dependslargely on the ability to synthesize and analyze new compounds. Givenapproximately 100 elements in the periodic table that can be used tomake compositions consisting of two or more elements, an incrediblylarge number of possible new compounds remains largely unexplored. Assuch, there exists a need in the art for a more efficient, economicaland systematic approach for the synthesis of novel materials and for thescreening of such materials for useful properties.

[0006] One of the processes whereby nature produces molecules havingnovel functions involves the generation of large collections (libraries)of molecules and the systematic screening of those collections formolecules having a desired property. An example of such a process is thehumoral immune system which in a matter of weeks sorts through some 10¹²antibody molecules to find one which specifically binds a foreignpathogen (Nisonoff et al., The Antibody Molecule (Academic Press, NewYork, 1975)). This notion of generating and screening large libraries ofmolecules has recently been applied to the drug discovery process.

[0007] Applying this logic, methods have been developed for thesynthesis and screening of large libraries (up to 10¹⁴ molecules) ofpeptides, oligonucleotides and other small molecules. Geysen et al., forexample, have developed a method wherein peptide syntheses are carriedout in parallel on several rods or pins (J. Immun. Meth. 102:259-274(1987), incorporated herein by reference for all purposes). Generally,the Geysen et al. method involves functionalizing the termini ofpolymeric rods and sequentially immersing the termini in solutions ofindividual amino acids. In addition to the Geysen et al. method,techniques have recently been introduced for synthesizing large arraysof different peptides and other polymers on solid surfaces. Pirrung etal. have developed a technique for generating arrays of peptides andother molecules using, for example, light-directed,spatially-addressable synthesis techniques (U.S. Pat. No. 5,143,854 andPCT Publication No. WO 90/15070, incorporated herein by reference forall purposes). In addition, Fodor et al. have developed a method ofgathering fluorescence intensity data, various photosensitive protectinggroups, masking techniques, and automated techniques for performinglight-directed, spatially-addressable synthesis techniques (Fodor etal., PCT Publication No. WO 92/10092, the teachings of which areincorporated herein by reference for all purposes).

[0008] Using these various methods, arrays containing thousands ormillions of different elements can be formed (U.S. patent applicationSer. No. 08/805,727, filed Dec. 6, 1991, the complete disclosure ofwhich is incorporated herein by reference for all purposes). As a resultof their relationship to semiconductor fabrication techniques, thesemethods have come to be referred to as “Very Large Scale ImmobilizedPolymer Synthesis,” or “VLSIPS™” technology. Such techniques have metwith substantial success in screening various ligands such as peptidesand oligonucleotides to determine their relative binding affinity to areceptor such as an antibody.

[0009] The solid phase synthesis techniques currently being used toprepare such libraries involve the sequential coupling of buildingblocks to form the compounds of interest. For example, in the Pirrung etal. method polypeptide arrays are synthesized on a substrate byattaching photoremovable groups to the surface of the substrate,exposing selected regions of the substrate to light to activate thoseregions, attaching an amino acid monomer with a photoremovable group tothe activated region, and repeating the steps of activation andattachment until polypeptides of the desired length and sequence aresynthesized. These solid phase synthesis techniques cannot readily beused to prepare many inorganic and organic compounds.

[0010] In PCT WO 96/11878, the complete disclosure of which isincorporated herein by reference, methods and apparatus are disclosedfor preparing a substrate with an array of diverse materials depositedin predefined regions. Some of the methods of deposition disclosed inPCT WO 96/11878 include sputtering, ablation, evaporation, and liquiddispensing systems. Using the disclosed methodology, many classes ofmaterials can be generated combinatorially including inorganics,intermetallics, metal alloys, and ceramics.

[0011] In general, combinatorial chemistry refers to the approach ofcreating vast numbers of compounds by reacting a set of startingchemicals in all possible combinations. Since its introduction into thepharmaceutical industry in the late 80's, it has dramatically sped upthe drug discovery process and is now becoming a standard practice inthe industry (Chem. Eng. News Feb. 12, 1996). More recently,combinatorial techniques have been successfully applied to the synthesisof inorganic materials (G. Briceno et al., SCIENCE 270, 273-275, 1995and X. D. Xiang et al., SCIENCE 268, 1738-1740, 1995). By use of varioussurface deposition techniques, masking strategies, and processingconditions, it is now possible to generate hundreds to thousands ofmaterials of distinct compositions per square inch. These materialsinclude high T_(c) superconductors, magnetoresistors, and phosphors.Discovery of heterogeneous catalysts will no doubt be accelerated by theintroduction of such combinatorial approaches.

[0012] A major difficulty with these processes is the lack of fast andreliable testing methods for rapid screening and optimization of thematerials. Recently, a parallel screening method based on reaction heatformation has been reported (F. C. Moates et al., Ind. Eng. Chem. Res.35, 4801-4803, 1996). For oxidation of hydrogen over a metallic surface,it is possible to obtain IR radiation images of an array of catalysts.The hot spots in the image correspond to active catalysts and can beresolved by an infrared camera.

[0013] Screening large arrays of materials in combinatorial librariescreates a number of challenges for existing analytical techniques. Forexample, traditionally, a heterogeneous catalyst is characterized by theuse of a micro-reactor that contains a few grams of porous-supportedcatalysts. Unfortunately, the traditional method cannot be used toscreen a catalyst library generated with combinatorial methods. First, aheterogeneous catalyst library synthesized by a combinatorial chemistrymethod may contain from a few hundred to many thousands of catalysts. Itis impractical to synthesize a few grams of each catalyst in acombinatorial format. Second, the response time of micro-reactors istypically on the order of a few minutes. The time it takes to reachequilibrium conditions is even longer. It is difficult to achievehigh-throughput screening with such long response times.

[0014] Another challenge with screening catalyst arrays is the low levelof components that may be present in the reactions. The consequence oflow level catalytic material is a low conversion rate. For example,oxidation of ethylene to ethylene oxide can be carried out over asilver-based catalyst (S. Rebsdat et al., U.S. Pat. Nos. 4,471,071 and4,808,738). For a surface-supported catalyst with an area of 1 mm by 1mm and the same activity as the industrial catalyst, only about 10 partsper billion (ppb) of ethylene are converted into the desired ethyleneoxide when the contact time is one second.

[0015] Detection of such low component levels in the presence of severalatmospheres of reaction mixture is a challenge to analytical methods.Many analytical techniques, including optical methods such as four-wavemixing spectroscopy and cavity ring-down absorption spectroscopy as wellas conventional methods such as GC/MS, are excluded because of poorsensitivities, non-universal detectability, and/or slow response.Therefore an apparatus and methodology for screening a substrate havingan array of materials that differ slightly in chemical composition,concentration, stoichiometry, and/or thickness is desirable.

SUMMARY OF THE INVENTION

[0016] The present invention provides methods and apparatus for therapid characterization and analysis of an array of materials usinginfrared imaging and spectroscopy techniques. Typically, each of theindividual materials on the array will be screened or interrogated forthe one or several material characteristics. Once screened, theindividual materials may be ranked or otherwise compared relative toeach other with respect to the material characteristic underinvestigation. Materials that can be compared using the methods andapparatus of the present invention include, for example liquids,dissolved organic or inorganic molecules, covalent network solids, ionicsolids and molecular solids. In particular, the present invention isdirected to characterization systems utilizing thermal imaging andinfrared spectroscopic imaging.

[0017] According to one aspect of the present invention, infraredimaging techniques are used to identify the active compounds within anarray of compounds by monitoring temperature change in the vicinity ofthe compound. Temperature change results from a reaction, eitherexothermic or endothermic in nature, and may be localized to specificcompounds within the library as well as the region of the substrateadjacent to the compounds in question. This same technique can also beused to quantify the stability of each new material within an array ofcompounds by observing the temperature change as a function of time. Bymeasuring the decay of activity through the change in temperature overtime for each site, the lifetime of catalysts, for example, can bequantified.

[0018] According to another aspect of the invention, identification andcharacterization of the condensed solid or liquid phase products isachieved, wherein library elements are characterized by their specificinfrared absorption or reflectance. Such materials may be the product ofreactions, for example, in the gas phase polymerization of ethylene tocondensed phase polyethylene or in the hydrolysis of liquiddimethyldichlorosilane to elastomeric polydimethylsiloxane. In oneembodiment specific molecular vibrations are evaluated by measuring theIR absorption. Typically, the radiation from a monochromatic infraredsource is passed through the library and the intensity of thetransmitted beam is measured as-a function of time during theprogression of a reaction. In an alternate embodiment, the library isirradiated with polychromatic infrared radiation and an infraredbandpass filter is used to confine the detection to specific wavelengthregions of the infrared spectrum.

[0019] In another aspect of the invention, heat transport properties aremeasured using the rate of heat dissipation in a library by observingthe transient change in temperature of the library elements withinfrared imaging. Preferably, a pulsed infrared source illuminates theback surface of the library while the front surface of the library ismonitored. Thus a measure of the thermal conductivity of each of theelements can be easily obtained.

[0020] According to a further aspect of the invention, identificationand characterization of material properties is achieved using atwo-dimensional infrared imaging system. The imaging systemsimultaneously monitors each element of the library, wherein eachindividual library element's temperature as well as its differencerelative to the surrounding elements reflects the activity and heat ofreaction of the specific library site.

[0021] A further understanding of the nature and advantages of theinventions herein may be realized by reference to the remaining portionsof the specification and the attached drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The file of this patent contains at least one drawing executed incolor. Copies of this patent with color drawing(s) will be provided bythe Patent and Trademark Office upon request and payment of thenecessary fee.

[0023]FIG. 1 illustrates an embodiment of the invention used todetermine the relative thermal diffusivities of the different materialson a library;

[0024]FIG. 2 illustrates a non-scanning configuration of the embodimentshown in FIG. 1;

[0025]FIG. 3 depicts a two-dimensional library of materials within wellson a substrate according to the invention;

[0026]FIG. 4 depicts a reaction chamber for monitoring thermal emissionof a polymerization reaction at a predefined pressure and temperature;

[0027]FIG. 5 depicts a thermal map of a polymerization reaction for 61elements in a library of elements within a pressurized reaction chamber;

[0028]FIG. 6 graphically illustrates the thermal evolution as a functionof time for the polymerization reactions of eleven wells of a library;

[0029]FIG. 7 depicts an infrared source irradiating a library ofcompounds on an infrared transparent substrate according to theinvention;

[0030]FIG. 8 depicts a polychromatic source irradiating a library ofcompounds on an infrared transparent substrate according to theinvention; and

[0031]FIG. 9 depicts a schematic of an IR imaging system according tothe invention.

DETAILED DESCRIPTION OF THE INVENTION Glossary

[0032] The following terms are intended to have the following generalmeanings as used herein.

[0033] Substrate: A substrate is a material having a rigid or semi-rigidsurface. In many embodiments at least one surface of the substrate willbe substantially flat. In some embodiments the substrate will containphysical separations between synthesis regions for different materials.Suitable physical separations include, for example, dimples, wells,raised regions, and etched trenches. According to other embodiments,small beads or pellets may be provided on the surface, either alone orwithin substrate surface dimples. The surface area of the substrate isdesigned to meet the requirements of a particular application.Typically, the surface area of the substrate is in the range of 1 cm² to400 cm². However, other sizes may be used with the present invention,for example surface areas as small as 0.001 cm² or as large as 10 m² arepossible.

[0034] Predefined Region: A predefined region is a localized area on asubstrate that is, was, or is intended to be used for the formation of aspecific material. The predefined region may be referred to, in thealternative, as a “known” region, a “reaction” region, a “selected”region, or simply a “region.” The predefined region may have anyconvenient shape, e.g., linear, circular, rectangular, elliptical, orwedge-shaped. Additionally, the predefined region can be a bead orpellet which is coated with the component(s) of interest. In thisembodiment, the bead or pellet-can be identified with a tag, such as anetched binary bar code, that can be used to identify which componentswere deposited on the bead or pellet. The area of the predefined regionsdepends on the application and is typically smaller than about 25 cm².However, the predefined regions may be smaller than 10 cm², smaller than5 cm², smaller than 1 cm², smaller than 1 mm², smaller than 0.5 mm²,smaller than 10,000 μm², smaller than 1,000 μm², smaller than 100 μm²,or even smaller than 10 μm².

[0035] Radiation: Radiation refers to energy with a wavelength between10⁻¹⁴ and 10⁴. Examples of such radiation include electron beamradiation, gamma radiation, x-ray radiation, ultraviolet radiation,visible light, infrared radiation, microwave radiation, and radio waves.Irradiation refers to the application of radiation to a material orobject.

[0036] Component: Component is used herein to refer to each of theindividual substances that are deposited onto a substrate. Componentscan act upon one another to produce a particular material. Componentscan react directly with each other or with an external energy sourcesuch as radiation, an electric field, or a magnetic field. A thirdmaterial or a chemical substance can also act upon components. Acomponent can be an element, a chemical, a material, or a mixture ofelements and chemicals. Components can form layers, blends or mixtures,or combinations thereof.

[0037] Source Material: The term source material is used herein to referto the original material from which a component was derived. Sourcematerials can be composed of elements, compounds, chemicals, molecules,etc. that are dissolved in a solvent, vaporized, evaporated, boiled,sublimed, ablated, etc., thus allowing the source materials to depositonto a substrate during the synthesis process.

[0038] Resulting Material: The term resulting material is used herein torefer to the component or combination of components that have beendeposited onto a predefined region of a substrate. The resultingmaterials may comprise a single component, or a combination ofcomponents that have reacted directly with each other or with anexternal source. Alternatively, the resulting material may comprise alayer, blend or mixture of components on a predefined region of thesubstrate. The resulting materials are screened for specific propertiesor characteristics to determine their relative performance.

[0039] Mixture or Blend: The term mixture or, interchangeably, blendrefers to a collection of molecules, ions, electrons, or chemicalsubstances. Each component in the mixture can be independently varied. Amixture can consist of two or more substances intermingled with noconstant percentage composition, wherein each component may or may notretain its essential original properties, and where molecular phasemixing may or may not occur. In mixtures, the components making up themixture may or may not remain distinguishable from each other by virtueof their chemical structure.

[0040] Layer: The term layer is used herein to refer to a material thatseparates one material, component, substrate or environment fromanother. A layer is often thin in relation to its area and covers thematerial beneath it. A layer may or may not be thin or flat, but once itis deposited it generally covers the entire surface such that itseparates the component or substrate below the layer from the componentor environment above the layer.

[0041] Heterogeneous catalysts: Heterogeneous catalysts enable catalyticreactions to occur with the reactants and catalysts residing indifferent phases. As used herein, heterogeneous catalysts include, butare not limited to, mixed metal oxides, mixed metal nitrides, mixedmetal sulfides, mixed metal carbides, mixed metal fluorides, mixed metalsilicates, mixed metal aluminates, mixed metal phosphates, nobel metals,zeolites, metal alloys, intermetallic compounds, inorganic mixtures,inorganic compounds, and inorganic salts.

[0042] Homogeneous catalysts: Homogeneous catalysts enable catalyticreactions to occur with the reactants and catalysts residing in the samephase. As used herein, homogeneous catalysts include, but are notlimited to, catalysts for the polymerization of one or more olefinic orvinyl monomers. The olefinic monomers include, but are not limited to,ethylene or alpha-olefins containing from 3 to 10 carbon atoms, such aspropylene, 1-butene, 1-pentane, 1-hexene, and 1-octene. The vinylmonomers include, but are not limited to, vinyl chloride, vinyl acetate,vinyl acrylate, methylmethacrylate, methyl vinyl ether, ethyl vinylether and acetonitrile. The catalysts employed to carry out apolymerization of one or more monomers of this type include, but are notlimited to, radical catalysts, cationic catalysts, anionic catalysts,and anionic coordination catalysts.

Generating Arrays of Materials

[0043] Generally, an array of materials is prepared by successivelydelivering components of the materials to predefined regions on asubstrate, and simultaneously reacting the components to form at leasttwo materials or, alternatively, the components are allowed to interactto form at least two materials. In one embodiment, for example, a firstcomponent of a first material is delivered to a first predefinedlocation on a substrate, and a first component of a second material isdelivered to a second predefined region on the same substrate.Simultaneously with or thereafter a second component of the firstmaterial is delivered to the first region on the substrate, and a secondcomponent of the second material is delivered to the second region onthe substrate. Each component can be delivered in either a uniform orgradient fashion to produce either a single stoichiometry or,alternatively, a large number of stoichiometries within a singlepredefined region. Moreover, the components can be delivered asamorphous films, epitaxial films or lattice or superlattice structures.The process is repeated, with additional components, to form a vastarray of components at predefined locations on the substrate.Thereafter, the components are simultaneously reacted to form at leasttwo materials or, alternatively, the components interact to form atleast two materials. As described herein, the components can besequentially or simultaneously delivered to the predefined regions onthe substrate using any of a number of different delivery techniques.

[0044] Numerous combinatorial techniques can be used to synthesize thevarious arrays of diverse materials on the substrate according to thepresent invention. For example, in one embodiment a first component of afirst and second material is delivered to the predefined regions on thesubstrate. Then a second component of the first and second materials isdelivered to the predefined regions on the substrate. This processcontinues for the other components (e.g., third, fourth, fifth, etc.components) and/or the other materials (e.g., third, fourth, fifth, etc.materials) until the array is complete. In another embodiment, the arrayis formed as previously described, but the resulting materials areformed immediately as the components contact each other on thesubstrate. In yet another embodiment, the array is formed as previouslydescribed, but after the various components are delivered to thesubstrate, a processing step is carried out which allows or causes thecomponents to interact to form layers, blends, mixtures, and/ormaterials resulting from a reaction between components. In still anotherembodiment, two or more components are delivered to the predefinedregions on the substrate using fast sequential or parallel deliverytechniques such that the components interact with each other beforecontacting the substrate. The resulting array of materials, each at adiscrete and known location on the substrate, comprises layers, blends,mixtures, and/or materials resulting from a reaction between components.

[0045] Essentially, any conceivable substrate can be employed in theinvention. The substrate can be organic, inorganic, biological,nonbiological, or a combination thereof. The substrate can exist asparticles, strands, precipitates, gels, sheets, tubing, spheres,containers, capillaries, pads, slices, films, plates, slides, etc. Thesubstrate can have any convenient shape, such as a disc, square, sphere,circle, etc. The substrate is preferably flat, but may take on a varietyof alternative surface configurations. For example, the substrate maycontain raised or depressed regions on which the synthesis of diversematerials takes place. The substrate and its surface preferably form arigid support on which to carry out the reactions described herein. Thesubstrate may be any of a wide variety of materials including, forexample, polymers, plastics, pyrex, quartz, resins, silicon, silica orsilica-based materials, carbon, metals, inorganic glasses, inorganiccrystals, and membranes. Upon review of this disclosure, other substratematerials will be readily apparent to those of skill in the art.Surfaces on the solid substrate can be composed of the same materials asthe substrate or, alternatively, they can be different (i.e., thesubstrates can be coated with a different material). Moreover, thesubstrate surface can contain thereon an adsorbent (for example,cellulose) to which the components of interest are delivered. The mostappropriate substrate and substrate-surface materials will depend on theclass of materials to be synthesized and the selection in any given casewill be readily apparent to those of skill in the art. In otherembodiments, the substrate can be a series of small beads or pellets. Aswith the single substrate having an array of materials thereon, each ofthe individual beads or pellets can be screened for materials havinguseful properties.

[0046] A variety of substrate systems are possible, including two- andthree-dimensional substrate systems. In some embodiments, thetwo-dimensional combinatorial catalysis library will be deposited eitheron a porous substrate, such as alumina, or on a non-porous substrate. Insome embodiments, the substrate will further contain a synthesissupport. The synthesis support can be made of alumina, silicon, quartz,zeolites, Teflon, silica and other oxides, etc. The synthesis supportmay be in the form of beads, discs or any other geometry in, forexample, one of the following substrate configurations: i) a poroussupport placed in wells wherein the reactants flow through the supportfrom the top of the wells out through a hole in the bottom of the wells(or flow may be in the reverse direction); ii) a porous support placedin wells wherein the reactants do not flow through from the top to thebottom of the wells, but only to and from the top of the wells; iii) anon-porous support placed in wells wherein the reactants flow around thesupport from the top of the wells out through a hole in the bottom ofthe wells (or flow may be in the reverse direction); iv) a non-poroussupport placed in wells wherein the reactants do not flow through fromthe top to the bottom of the wells, but only to and from the top of thewells; or v) a porous or non-porous support not contained in wellswherein the reactants are deposited directly onto the substrate surface.

[0047] Generally, physical masking systems can be employed incombination with various deposition techniques in order to applycomponents onto a substrate in a combinatorial fashion, thereby creatingarrays of resulting materials at predefined locations on the substrate.The arrays of resulting materials will usually differ in composition,stoichiometry and/or thickness across the substrate. The components can,for example, be dispensed to the substrate in the form of a gas, aliquid or a powder. Suitable deposition techniques include, but are notlimited to, sputtering, electron-beam and thermal evaporation, laserdeposition, ion beam deposition, chemical vapor deposition, andspray-coating. In solution phase deposition techniques include, forexample, sol/gel methods, discrete liquid dispensing techniques (e.g.pipettes, syringes, ink jets, etc.), spin coating with lithography,microcontact printing, spraying with masks and immersion impregnation.Moreover, such dispenser systems can be manual or, alternatively, theycan be automated using, for example, robotics techniques. A morecomplete description of representative arrays of materials and systemsand methods for generating such arrays of materials can be found incommonly assigned, co-pending patent applications “The CombinatorialSynthesis Of Novel Materials”, Publication No. WO 95/13278, filed Oct.18, 1995; “Systems and Methods for the Combinatorial Synthesis of NovelMaterials,” patent application Ser. No. 08/841,423. filed Apr. 22, 1997;and “Discovery of Phosphor Materials Using Combinatorial SynthesisTechniques,” provisional patent application Serial No. 60/039,882, filedMar. 4, 1997; the complete disclosures of which are incorporated hereinby reference for all purposes.

[0048] In some embodiments of the present invention, after thecomponents have been deposited onto predefined regions on a substrate,they are reacted using a number of different techniques. For example,the components can be reacted using solution based synthesis techniques,photochemical techniques, polymerization techniques, template directedsynthesis techniques, epitaxial growth techniques, by the sol-gelprocess, by thermal, infrared or microwave heating, by calcination,sintering or annealing, by hydrothermal methods, by flux methods, bycrystallization through vaporization of solvent, etc. Furthermore, eachpredefined region on the substrate can be heated simultaneously orsequentially using heat sources such as focussed infrared radiation,resistive heating, etc. Reactants can, for example, be dispensed to thelibrary of elements in the form of a gas or a liquid. Other usefultechniques that can be used to react the components of interest will bereadily apparent to those of skill in the art. Additionally, componentscan react with each other instantly, upon contacting each other, or inthe air before contacting the substrate. The components can also formlayers, blends or mixtures, in the air or on the substrate, rather thanreacting with each other.

[0049] Once prepared, the array of resulting materials can be screenedfor useful properties using the methods described herein. Either theentire array or, alternatively, a section thereof (e.g., a row ofpredefined regions) can be screened using parallel or fast sequentialscreening. In some embodiments, a predefined region on the substrateand, therefore, the area upon which each distinct material issynthesized, is smaller than about 25 cm², less than 10 cm², less than 5cm², less than 1 cm², less than 1 mm², or less than 0.5 mm². In otherembodiments, the regions have an area less than about 10,000 μm², lessthan 1,000 μm², less than 100 μm², or less than 10 μm². Accordingly, thedensity of regions per unit area will be greater than 0.04 regions/cm²,greater than 0.1 regions/cm², greater than 1 region/cm², greater than 10regions/cm², or greater than 100 regions/cm². In other embodiments, thedensity of regions per unit area will be greater than 1,000 regions/cm²,greater than 10,000 regions/cm², greater than 100,000 regions/cm², orgreater than 10,000,000 regions/cm².

[0050] In some embodiments, the screening systems of the presentinvention will be used to screen a single substrate having at least 9different materials. In other embodiments, the screening system scans asingle substrate having more than 50, 100, 10³, 10⁴, 10⁵, 10⁶, or morematerials synthesized thereon. In some embodiments, the substrate willcomprise arrays of materials with as few as two components, although thesubstrate can have materials with 3, 4, 5, 6, 7, 8 or more componentstherein. The substrate can be screened for materials having usefulproperties and/or the resulting materials can be ranked, or otherwisecompared, for relative performance with respect to useful properties orother characteristics. Resulting materials include, but are not limitedto, covalent network solids, ionic solids and molecular, inorganicmaterials, intermetallic materials, metal alloys, ceramic materials,organic materials, organometallic materials, non-biological organicpolymers, composite materials (e.g., inorganic composites, organiccomposites, or combinations thereof), or homogeneous or heterogeneouscatalysts. Again, once useful resulting materials have been identifiedusing the methods of the present invention, a variety of differentmethods can be used to prepare such materials on a large or bulk scalewith essentially the same structure and properties. Properties which canbe screened for include, but are not limited to, electrical, thermal,mechanical, morphological, optical, magnetic, chemical, conductivity,super-conductivity, resistivity, thermal conductivity, anisotropy,hardness, crystallinity, optical transparency, magnetoresistance,permeability, frequency doubling, photoemission, coercivity, dielectricstrength, or other useful properties which will be apparent to those ofskill in the art upon review of this disclosure. Importantly, thesynthesizing and screening of a diverse array of resulting materialsenables new compositions with new physical properties to be identified.

[0051] Given the chemical complexity of catalytic systems, the lack ofpredictive models, the number of possible combinations of metals,counterions, ligands, and supports, and the time consuming process ofevaluating the performance of each catalyst formulation utilizingconventional laboratory pilot reactors, it is not surprising that thesearch for the optimum catalyst is a time consuming and inefficientprocess. Thus, a combinatorial approach to the discovery andoptimization of catalytic systems, which combines the synthesis ofcatalyst libraries with the screening tools of this invention, is usefulfor accelerating the pace of research in this field. The catalystlibraries of the present invention can include organic (e.g., catalyticantibodies), organometallic, heterogeneous or solid state inorganicarray elements. Organometallic catalyst libraries which can be screenedfor useful catalytic properties include, but are not limited to, thosedescribed in co-pending U.S. patent application Ser. No. 08/898,715,filed Jul. 22, 1997, which is hereby incorporated by reference for allpurposes.

[0052] Catalyst libraries comprising inorganic (e.g., heterogeneous andsolid state inorganic) materials can also be screened for usefulproperties using the methods of this invention. Catalyst libraries cancomprise powders, impregnated solid supports, inorganic films andmonoliths, or crystals that are spatially separated within a substratesystem (e.g., wells, flat surfaces). Solid state inorganic materialsuseful as heterogeneous catalysts are well known in the chemicalindustry. Heterogeneous catalysts enable catalytic reactions to occurwith the reactants and catalysts residing in different phases andinclude, but are not limited to, mixed metal oxides, mixed metalnitrides, mixed metal sulfides, mixed metal carbides, mixed metalfluorides, mixed metal silicates, mixed metal aluminates, mixed metalphosphates, nobel metals, zeolites, metal alloys, intermetalliccompounds, inorganic mixtures, inorganic compounds, and inorganic salts.Heterogeneous catalyst systems typically comprise metals, metal oxides,metal sulfides, and other metal salts, can be supported on a carrier(e.g., alumina, silica of controlled particle size and porosity), andcan be used in bulk.

[0053] Heterogeneous catalysts can be prepared by a number of methodswhich are well known in the art and include mixing reactive solutions,impregnation of solutions of metal salt precursors onto or into solidcarriers, coprecipitation, and mixing colloidal dispersions. Thesemethods yield chemically complex, multicomponent solid products that canbe further treated with reducing agents, oxidizing agents and otherthird components and modifiers to produce optimized materials.

[0054] Once an array of catalysts is formed, the screening methods ofthe present invention can be used to characterize the catalyticproperties of the various compounds by observing, for example, activity,lifetime and selectivity for a variety of catalytic transformations. Forpurposes of this invention, a catalyst is defined as any material thataccelerates the rate of a chemical reaction and which is either notconsumed during the reaction or which is consumed at a rate slower (on amolar basis) than the reaction that is being catalyzed. Examples ofcatalytic reactions/transformations include, but are not limited to,total oxidations (e.g., the conversion of CO into CO₂ using oxygen, orNO_(x), for simultaneous reduction of the NO_(x)), selective oxidations(e.g., epoxidations of olefins), reductions (e.g., hyrdogenation ofunsaturated species), polymerizations (e.g., ethylenecopolymerizations), dimerization (e.g., ethylene to butene),trimerization, oligomerization, decompositions (e.g., conversion ofNO_(x) into N₂ and O₂), hydrosilation, carbonylations, hydrocynation,hydroformylation, isomerization, metathesis (e.g., of olefins andacetylenes), carbon-hydrogen activation, cross coupling, Friedel-Craftsacylation and alkylation, hydration, and Diels-Alder reactions.

Thermal Imaging of Combinatorial Libraries

[0055] The thermodynamic evaluation of combinatorial chemical librariesprovides critical information useful in the discovery and optimizationof new materials. Thermodynamic characterization relates the observablebulk properties of a material (volume, enthalpy, heat capacity, freeenergy, heat of reaction, catalytic activity, thermal conductivity,etc.) to imposed external conditions (pressure, temperature,composition, etc.). In principle, thermodynamic measurements are takenand the results tabulated and used to monitor trends in the observedsystems under different conditions.

[0056] The temperature of an entire library of materials may bemonitored with an infrared camera as a measure of the thermodynamicquantities associated with the materials, the measurements performedeither serially or in parallel. Commercial position sensitive systemssuch as infrared focal plane arrays, for example comprised of InSb orHgCdTe detectors, have a sensitivity of better than ±0.05° C. over therange of temperatures from −50° C. to 800° C. and a spatial resolutionof better than 1 mm depending on the optics. The speed of the dataacquisition from a commercial infrared camera is as high as 120 framesper second, thus providing sufficient speed to follow most chemicalreactions and thermal diffusion transients.

[0057] In a specific embodiment, the infrared camera is used to monitorthe heats of reaction of a combinatorial library under various externalconditions such as temperature and gas flow. For example, if a solidcatalyst library and its surrounding support in a two-dimensionallibrary are exposed to a reactant, a measurable heating of thesurroundings may occur depending on the activity of the chemicalprocess. In the case of a catalyst, the activity of the catalyst on thesupport will be represented through the energy released or absorbed asheat during the chemical reaction between the catalyst and the exchangegas. In a combinatorial library, elements are nearly identical inthermal mass such that measurements of the heat evolved by one elementin the library relative to others within the library reveals trendsuseful in the characterization of the chemical processes induced bythese materials.

[0058] According to another embodiment of the invention illustrated inFIG. 1, the relative thermal diffusivities of the different materials ona library are measured, thus providing a measure of the materialdensity, thermal conductivity, and specific heat for the individualmaterials. The different materials 101 are affixed to a uniformsubstrate 103, for example using a deposition process. A modulated heatsource 105 is directed toward the underside of the library, eitherdirectly adjacent to a single element or in such a manner as tosimultaneously and uniformly irradiate the entire library. An IRdetector 107 scans the library, either by repositioning the detector orby repositioning the library relative to the detector. Detector 107monitors the temperature change of library materials 101 in response tothe modulation of heat source 105. If heat source 105 does notsimultaneously and uniformly irradiate the entire library, it must bescanned in conjunction with detector 107, thus insuring that themonitored thermal diffusivities correspond to the same heat input. Tomaximize the sensitivity of this configuration, substrate 103 should beas thin and thermally transparent as possible.

[0059]FIG. 2 illustrates a second configuration of the embodiment shownin FIG. 1. In this configuration, a modulated heat source 201simultaneously and uniformly irradiates the entire substrate 103, andthus all library materials 101. A position sensitive IR detector array203 monitors the temperature change of all library elements 101, thusremoving the necessity for a translation system.

[0060]FIG. 3 illustrates a two-dimensional library 300 of materialsaccording to one embodiment of the invention. The individual libraryelements are contained within a plurality of reaction wells 301 in asubstrate 303. Substrate 303 is placed within a sealed reaction chamber(not shown) which is subsequently filled with selected gases andpressurized. Substrate 303 is then heated in situ. Windows 305 and 307are made of an infrared transparent medium (e.g., BaF₂, CaF₂, NaCl,etc.) capable of holding the pressurized gas inside the chamber. Sincewindows 305 and 307 are transparent, thermal imaging techniques can beused to monitor, in parallel, the heat of reaction of the array undervarious external conditions.

[0061] Measuring the heat of reaction through temperature changes is auseful technique for screening catalytic rate. Though insensitive toproducts, this method provides a parallel, high-throughput screen whenactivity is of interest. For condensed phase products of bothhomogeneous and heterogeneous catalysis, the products themselves are inthermal contact with the catalyst. Thus, infrared emission imaging ofthe library elements provides a unique means of screening largelibraries in parallel. If large differences in emissivity are observedfor the individual library elements, an alternate embodiment may be usedin which the imaging is performed from the side of the substrateopposite the library elements. In this configuration the imaging isperformed through a material, such as graphite, having a uniformemissivity. As a result, a significantly better signal to noise ratio isachieved. However, since relative changes in temperature are ofinterest, emissivity differences do not preclude the usefulness of themeasurement.

[0062] In the condensed phase detection system described above, theproducts, catalyst and support will all change temperature. However, inthe gas phase the temperature variation is limited to the catalyst andsupport. The temperature of each individual library element as well asthe difference in temperature relative to the surrounding elementsreflects the activity of a specific library site and the heat ofreaction. Preferably the catalyst support has minimal thermal mass andthe catalyst surface area for each library element is nearly identical.

[0063] In order to perform a measurement, the sample chamber, library,and structure is first equilibrated to a uniform temperature. An inertgas fills the chamber at a pre-defined pressure. At a time t equals 0,the desired reactant gas is leaked into the chamber and the substratetemperature is monitored. Preferably the substrate temperature ismonitored at periodic intervals although continuous monitoring may alsobe used. The rise or fall in temperature of the thermal mass supportingthe catalyst is a direct measure of the exothermic or endothermiccatalytic activity of the site.

[0064] As an estimate of the temperature change expected, if amicrojoule is deposited in a 1 mm×1 mm×0.0001 mm region of material, atemperature change of approximately 0.5 K is expected. The reaction ofethylene and hydrogen to ethane produces 120 KJ/mole and, therefore, 1microjoule requires only the reaction of 5×10¹² molecules. Many timesthat number of molecules will react per second on a typical 1 mm×1mm×0.0001 mm porous support or on a non-porous 1 mm×1 mm×0.000001 mmfilm. In another embodiment, individual elements can be monitored inseries using position insensitive temperature detection technology orsingle element scanned detectors.

EXAMPLE

[0065] The following example indicates the use of thermal imagingaccording to the invention to monitor thermal emission during apolymerization reaction. FIG. 4 illustrates a reaction chamber 400 formonitoring thermal (i.e., infrared) emission at a predefined pressureand temperature. Thus system 400 can be used to screen libraries ofpotential catalysts for activity under polymerization conditions.Typically a library of catalysts, such as the substrate shown in FIG. 3,is placed in system 400. The catalysts, solvents, initiators, andadditional components necessary to carry out the polymerization reactionare placed into wells within thermostatted substrate 303, which iscapable of reaching elevated temperatures, such as 100° C., under anoverpressure of gas, such as ethylene gas at 40 psig. The temperature ofeach well is monitored through an IR transparent window 401 with aposition sensitive imaging system 403. Preferably imaging system 403captures thermal maps of the library at fixed intervals in time. FIG. 5illustrates a representative thermal map 500. The library imaged inthermal map 500 includes 61 elements. As illustrated, highertemperatures are indicated by an increase in image intensity as well asa change in color from blue to red.

[0066] The graph illustrated in FIG. 6 provides the temperature ofeleven representative library elements as a function of time. If higherresolution is required, more frequent data points can be obtained simplyby decreasing the time intervals between IR images.

Differential Thermal Analysis

[0067] Changes in the structure and bonding of a chemical compositionduring a transition from one thermodynamically stable phase to anotherresults in heat being evolved (exothermic process) or absorbed(endothermic process). Therefore during a phase transition thetemperature of the sample of interest may change or the rate oftemperature change may increase or decrease. Traditionally, differentialthermal analysis is performed in a sealed environment where thetemperature of the material being measured is compared to thetemperature of a standard material (e.g., α-Al₂O₃) having no phasetransition as the temperature is varied over the range of interest. Indifferential thermal analysis, the temperature of the standard materialis subtracted from the temperature of the sample material to yield thetemperature difference. Then a graph is made of the temperature versusthe derived temperature difference.

[0068] In another embodiment of the invention, differential thermalanalysis of combinatorial libraries is performed using an infraredcamera. The infrared camera monitors the temperature of every libraryelement in parallel and compares it to the temperature of a knownstandard material deposited within the field of view of the camera andsubjected to the same physical conditions as the library elements. Inthis way, complicated phase relationships are measured for largelibraries of materials by heating or cooling the library and measuringchanges in the differential temperature or in the slope of thedifferential temperature versus the actual temperature.

Rapid Screening of Combinatorial Libraries with Infrared Spectroscopy

[0069] Until now there has been no known device capable ofcharacterizing in parallel the structure activity relationships for alarge number of chemical reactions on a time scale relevant to the speedof most polymerization and catalytic reactions. Most existinginstruments characterize one sample at a time, or a number of samples inseries at a rate that is slower than most chemical reactions.

[0070] The present invention provides a system for simultaneouslycharacterizing the reaction products from a library of differentcatalysts. In one example, the products are polymers and informationabout polymer structure may be obtained. Preferably the system operatesin the near-IR (NIR) (12,500-4000 cm⁻¹) and mid-IR regions(4000-200cm⁻¹) of the spectrum.

[0071] Absorption bands in the near-IR region are caused by overtonesand combinations of fundamental molecular vibration bands commonly foundin the mid-IR. Thus the near-IR region is a somewhat simpler spectrumfor a computer to fit analytically. In general, the relationship betweenchanges in the absorption spectrum and changes in the physicalproperties of the polymers is determined empirically with the aid of acomputerized fit of the near-IR spectrum. The relative nature of theabsorption analysis in the near-IR makes it suitable for high-throughputscreening. Polymer molecular weight, melt index, tacticity, branchingratio, and the degree of conversion are examples of information that canbe obtained from analysis of the near-IR spectrum.

[0072] The mid-IR region of the spectrum provides much more informationabout the vibrational character of polymers. For example, structuralparameters such as the frequency of methyl, butyl, and ethyl branches inpolyethylene can be determined from changes in the peak absorbances inthe mid-IR region.

[0073] There are several configurations of the invention that can beused to measure the infrared absorption spectrum of a combinatoriallibrary, examples of which are described below.

[0074] Infrared Absorption Spectroscopy Using a Monochromatic Source

[0075] According to one embodiment of the invention, specific molecularvibrations are evaluated by infrared absorption. Because C═C stretchmodes have specific absorptions at 1650 and 2200 cm⁻¹, monitoring therelative change in absorption at those frequencies over a libraryprovides a measure of the relative change in the number of C═C bonds inthe system. Therefore, the change in absorption reflects structuralchanges that occur during polymerization, for example during thepolymerization of ethylene.

[0076]FIG. 7 illustrates a system in which a monochromatic infraredsource 700 irradiates a library of compounds 705 contained on asubstrate 710. Substrate 710 is made of an infrared transparent materialsuch as BaF₂, CaF₂, or NaCl, and may or may not include wells, as shown.Source 700 can be a monochromatic infrared source tuned to a specificwavelength using selective filters, for example, or any other tunablemonochromatic source. The intensity of the portion of IR beam 715passing through library element 705 and substrate 710 is detected as afunction of time by an IR sensor 720. IR sensor 720 may be comprised,for example, of either HgCdTe or InSb detectors. By monitoring theinfrared absorption as a function of time, the progression of thereaction can be monitored.

[0077] Source 700 can be directed through individual library elementsone-by-one in a serial fashion, or a large area source beam can bepassed through the entire library. Similarly, infrared detection system720 may be a single infrared detector scanned over the library in aserial manner, or it may be a position sensitive imaging systemmonitoring the absorption of all of the library elements in a parallelmanner.

[0078] Infrared Absorption Spectroscopy using a Polychromatic Source

[0079] According to another embodiment of the invention, the absorptionof specific molecular vibrations in the infrared is measured afterirradiating a library with polychromatic radiation. After absorption bythe library, the radiation passing through the library elements isfiltered so as to detect a desired wavelength region using selectivebandpass filters. FIG. 8 illustrates a system using a polychromaticsource 800 to irradiate a library of compounds 705 on infraredtransparent substrate 710. In this embodiment, one or more filters 805are placed between the library and the detector system 810. As in theabove example, the system can use either a broad area beam to irradiatethe entire library or a smaller beam can be used to irradiate somesubset of library elements, for example a single element. Similarly,filters 805 and detection system 810 can scan over the library in aserial fashion, or the entire library can be monitored using a positionsensitive detector. Filters 805 can be either separate from, or integralwith, detection system 810.

[0080] Infrared Absorption Spectroscopy Using an FT-IR Imaging System

[0081] In another embodiment of the invention, a large number ofchemical reactions can be characterized on a time scale of minutesrather than hours. The system generally includes a Fourier transforminfrared (FT-IR) spectrometer, a high-speed infrared camera, and acomputer. In an embodiment configured for operating in a transmissionmode, a modified FT-IR spectrometer generates a modulated infrared beamof radiation that is focused onto the combinatorial library where itinteracts with the compounds of interest. After interaction with thelibrary, the beam is re-focused onto the focal plane array (FPA) of ahigh-speed infrared camera. The FPA acts as an area detector to captureradiation for every position within the field of view, allowing for trueparallel detection of the IR spectra for large combinatorial libraries.

[0082]FIG. 9 schematically illustrates an IR imaging system according tothe present invention. The system includes an IR source/interferometer901, a sample/library region 903 and an infrared camera 905 coupled to acomputer 907. The system requires a sufficiently intense source ofmodulated IR radiation to uniformly illuminate the extended sampleregion of interest. Interferometer 901 modulates the signal frequencyinto a range detectable by camera 905. After leaving interferometer 901,the IR beam is expanded, for example using lens 909, prior tointeracting with sample 903. Suitable collection optics 911 focuses theIR beam passing through sample 903 onto the FPA of camera 905. Infraredcamera 905 captures position sensitive infrared profiles sequentially intime at a rate determined by the desired spectral resolution andspectral bandwidth, preferably at a rate of 60 frames/sec or greater.The sequential intensity profiles are transformed (using Fourieranalysis) into a complete infrared spectrum with the aid of computer907.

[0083] Infrared source 901 of the imaging FT-IR setup generally includesa radiation source and signal processing equipment (e.g.,interferometer). A typical source is a glowbar or some other heatedmaterial capable of producing a polychromatic spectrum covering theinfrared region of interest.

[0084] In an FT-IR system, light from a point source is renderedparallel by a collimator and passed on to a beamsplitter. The two beamsformed by the beamsplitter travel to the mirrors and are reflected back.The beams then recombine at the beamsplitter where they interfere toproduce an interferogram that is directed at the combinatorial library.After interacting with the library, the infrared radiation passingthrough the library is focused onto the detector. The detector recordsan intensity signal that depends on the path difference imposed by thetravel to and from the mirrors and the absorption by the materials inthe combinatorial library. The distance from the beamsplitter to themirrors is arbitrary; what matters is the difference in the lengths ofthe paths.

[0085] One of the mirror arms in the interferometer is moved at aconstant velocity, V. When illuminated by a monochromatic source, thedetector will see a periodically varying cosine wave. The electricalfrequency f of this wave is determined by the rate of change of the pathdifference dD/dt. Since dD/dt is simply 2V, f is equivalent to 2nV.Therefore, a Michelson interferometer can be considered to be a form offrequency transducer that converts optical frequencies which aretypically too fast for a detector to monitor down to electricalfrequencies that can have any value determined by the mirror velocity V.

[0086] The path difference is easily determined with the aid of a laser,for example a HeNe laser. The laser beam is sent through theinterferometer concurrently with the IR radiation. As the pathdifference changes, the monochromatic laser light forms a cosine wave ata detector. By counting the number of maxima (fringes) in the patterngenerated by the recombined beam, the path difference can be measuredvery precisely, as is well known in the art.

[0087] There are two fundamentally different approaches to the controlof a FT-IR spectrometer. In the first, the mirror is moved at a constantvelocity, resulting in a continuous output at the detector. Mostcommercial FT-IR spectrometers use an interferometer that has continuousscanning of the interferometer mirror. In the second approach, themirror is stepped between sample points as quickly as possible. At eachstep, the mirror is held in position for the desired integration time.This approach, known as step scanning, has two distinct advantages overcontinuous scanning. First, measuring the mirror position and thereforethe path difference is easier and more precise. Second, in the preferredembodiment the imaging system relies on an infrared camera with a FPA ofroughly 256×256 (65,536) elements. Due to the size of the FPA, the rateat which data can be unloaded from the array is limited. Step scanningallows for a slight pause as the mirror steps to the next positionduring which the data can be unloaded from the FPA. A triggering signalis provided to the IR camera when the mirror reaches a given position.The obvious drawback of a step scanning interferometer relative to acontinuous scanning interferometer is the speed at which data can beobtained.

[0088] Commercial step scanning interferometers operating in the mid-IRtypically use a glowbar source capable of producing a power density of0.7 mW/mm² (i.e., 35 mW over an 8 mm diameter beam). Therefore,expansion of the standard beam over the full size of a polymer libraryrequires increasing the power output of the source to maintain the samepower density across each element in the library. For example,illuminating a 40 mm diameter area at 0.7 mW/mm² requires a glowbarpower of 880 mW, a factor of 25 greater than a typical glowbar.Furthermore, as the power output of the source is increased, the powerhandling capabilities of the interferometer optics must be similarlyincreased. One approach for a high intensity source is to utilizemultiple glowbar sources with an appropriate ellipsoidal mirror. Theintensified beam is then collimated.

[0089] Expansion optics 909 should be capable of expanding the highintensity beam from the interferometer without an appreciable powerloss. This is possible with laser-bean expanders that have IRtransmission coatings optimized for the spectral range of the FPA. Ifdesired, fiber optics can be used to confine the radiation to thereaction wells, therefore reducing the total power required byeliminating the power that is normally wasted on the dead space betweenthe reaction wells.

[0090] According to the present invention, the spectroscopic imagingsystem provides parallel measurement of the infrared spectrum of acombinatorial library of compounds. Therefore, the modulated IRradiation from the interferometer preferably interacts with each samplein the library before it reaches the IR camera. There are two differentsample configurations that are useful far polymer analysis: (i) postpolymerization analysis of polymer films that can be void of solvent and(ii) in situ analysis of polymerization reactions where solvent may bepresent. Both configurations can be performed with transmissionspectroscopy. However, the restraints on the samples differ for eachconfiguration due to the detection limits of the FPA and interactionswith the solvent.

[0091] Post reaction analysis of thin-film libraries is significantlyeasier than the in situ analysis. Aside from eliminating the solventpeaks from the spectrum, the signal to noise ratio is maximized byincreasing the integration time on the FPA since the time constraintsplaced on the system while attempting to track a chemical reaction areeliminated. The signal to noise ratio is further maximized due to theinherent increase in absorption resulting from a high concentration ofpolymer interacting with the source radiation. A thin-film library canbe robotically deposited on a suitable IR transmitting substrate andthen imaged in parallel very easily with this system.

[0092] Monitoring a polymerization reaction is substantially morecomplicated. First, a reaction vessel capable of holding the polymersolutions must be constructed with the following criteria: (i) at leastone side of the reaction vessel must have an IR transparent material toallow the radiation to pass through the sample; (ii) the generalfeatures of a polymerization reactor must be maintained (e.g.temperature control, mixing/agitation, etc.); and (iii) the thicknessand therefore the IR path length of the reaction vessel must be smallenough that the radiation is not completely attenuated, but still longenough to allow for a measureable amount of absorption. For example, a 6mm diameter×10 mm long cylinder (having a volume about equal to 0.3 cc)in a standard plate is used for the near-IR, and a similar plate designwith a cylinder having a 1 mm path length is used for the mid-IR. Anexample of one design is schematically illustrated in FIG. 3.

[0093] The sample chamber should be isolated from stray IR radiation.For example, a person walking into the area where the experiment isbeing performed provides a measurable amount of reflected heat radiationthat may be picked up by the FPA. A closed sample chamber similar tothose found in commercial FT-IRs is typically acceptable.

[0094] The FPA of the camera should have a high signal to noise ratio tomeasure the weak signal coming from each element (i.e., reactor) in thelibrary. The exact limits are set by the amount of intensity provided bythe source and by the amount lost in the system. Commercial IR camerashave FPAs made primarily of cooled InSb and HgCdTe detectors with fixednoise characterstics. Since the camera is typically purchased as afinished package, the sensitivity of the FPA is not the important factorrather, it is the sensitivity of the entire camera (FPA, electronics,filtering, etc.) that is the critical design factor.

[0095] In order to track chemical reactions with this device, the IRspectrum needs to be sampled at certain time intervals that may rangefrom every 20 seconds to a single measurement depending on the desiredinformation (i.e. in situ measurements vs. film characterization).Capturing the IR spectrum for every element in the library every 20seconds requires a high speed IR camera; the data acquisition rate ofthe camera is determined by the strength of the signal, the desiredspectral bandwidth, and the resolution. Although the true time requiredto obtain a spectrum relies on the data acquisition rate and on thecomputer processing, the ability of the IR camera to operate at fasterthan 120 frames/sec allows a sufficient number of interferograms to besampled to reconstruct the spectrum rapidly.

[0096] The images captured by the IR camera should be collected andanalyzed to create a series of interferograms (intensity versus time)for each element in the image corresponding to an element in thecombinatorial library. The interferograms must be transformed back to amore useful intensity versus wavelength representation with the aide ofa Fourier transform performed by the computer. In order to perform theFourier transform, the computer must know precisely the time or mirrorposition corresponding to each image. It is therefore necessary to havean electronic trigger on the interferometer to trigger the camerashutter. In this way a series of plots of absorbance versus wavelengthcan be constructed for every element within the field of view of theinfrared camera.

[0097] It is to be understood that the above description is intended tobe illustrative and not restrictive. Many embodiments will be apparentto those of skill in the art upon reading the above description. Thescope of the invention should, therefore, be determined not withreference to the above description, but should instead be determinedwith reference to the appended claims, along with the full scope ofequivalents to which such claims are entitled. The disclosures of allarticles and references, including patent applications and publications,are incorporated herein by reference for all purposes.

What is claimed:
 1. A method of characterizing materials comprising thesteps of: providing a substrate; synthesizing an array of materials onsaid substrate; providing at least one reactant gas, wherein saidreactant gas is in contact with said array of materials; activating atleast one of said materials on said array with a heating source; andperiodically monitoring an infrared emission from said activatedmaterial with an infrared camera, wherein said infrared camera outputs aseries of signals corresponding to an emission intensity varying withtime of said activated material.
 2. The method of claim 1, wherein saidheating source and said infrared camera scan, in unison, said array ofmaterials.
 3. The method of claim 1, wherein said entire array ofmaterials is simultaneously monitored by said infrared camera.
 4. Amethod of characterizing materials comprising the steps of: providing asubstrate; synthesizing an array of materials on said substrate;enclosing said array in a chamber; filling said chamber with an inertgas at a predefined pressure; equilibrating said chamber and said arrayto a uniform temperature; leaking at least one reactant gas into saidchamber; and monitoring an infrared emission from said array ofmaterials with an infrared camera, wherein said infrared camera outputsa series of signals corresponding to an emission intensity as a functionof time for each of said materials.
 5. A method of characterizingmaterials comprising the steps of: providing a substrate; synthesizingan array of materials on said substrate; enclosing said array in achamber; enclosing a standard material in said chamber; monitoring aninfrared emission from each of said materials of said array and of saidstandard material with an infrared camera while at least oneenvironmental condition within said chamber is varied, wherein saidinfrared camera outputs a series of signals corresponding to atemperature of each of said materials as a function of time, and whereinsaid environmental condition is selected from the group consisting ofchamber temperature, chamber pressure, and chamber gas composition; andcalculating a temperature difference between each of said materials ofsaid array and said standard material.
 6. A method of monitoring theinfrared absorption spectrum of a library of materials contained in anarray, said method comprising the steps of: providing a substrate;synthesizing said array of materials on said substrate; irradiating saidarray of materials with a monochromatic infrared radiation source; andmonitoring material absorption for each of said materials of said arrayas a function of time.
 7. The method of claim 6, wherein saidmonochromatic infrared radiation source sequentially irradiates saidmaterials of said array.
 8. The method of claim 6, wherein saidmonochromatic infrared radiation source simultaneously irradiates saidmaterials of said array.
 9. A method of monitoring the infraredabsorption spectrum of a library of materials contained in an array,said method comprising the steps of: providing a substrate; synthesizingsaid array of materials on said substrate; irradiating said array ofmaterials with a polychromatic infrared radiation source; filteringradiation passing through said array of materials with at least oneoptical filter, wherein said filter is selected to pass the desiredwavelength spectra; and monitoring material absorption for each of saidmaterials of said array as a function of time.
 10. A method ofcharacterizing a library of materials contained in an array, said methodcomprising the steps of: providing a substrate; synthesizing said arrayof materials on said substrate; simultaneously irradiating said array ofmaterials with a modulated beam of infrared radiation, wherein at leasta portion of said modulated beam interacts with at least one of saidmaterials; focussing radiation passing through said array onto a focalplane array of a high speed infrared camera, wherein said infraredcamera captures position sensitive intensity profiles sequentially intime; and transforming said sequential intensity profiles into acomplete infrared spectrum using Fourier analysis.
 11. The method ofclaim 10, wherein said infrared camera captures position sensitiveintensity profiles at a rate of at least 60 frames per second.
 12. Themethod of claim 10, wherein a continuous scanning interferometer is usedto vary the wavelength of the modulated beam of infrared radiation. 13.The method of claim 10, wherein a step scanning interferometer is usedto vary the wavelength of the modulated beam of infrared radiation. 14.A method of characterizing materials comprising the steps of: providinga substrate; synthesizing an array of materials on said substrate;irradiating said array of materials with infrared radiation of a firstwavelength; and monitoring an infrared emission from each of saidmaterials of said array of materials, wherein said infrared emission isat a second wavelength.
 15. A system for monitoring the heats ofreaction of a combinatorial array of materials, comprising: an IRtransparent substrate containing said combinatorial array of materials;a reaction chamber enclosing said IR transparent substrate; at least onereactant gas, wherein said reactant gas is coupled to said reactionchamber through a valve; and an infrared camera imaging saidcombinatorial array of materials, wherein said infrared camera outputs aseries of signals corresponding to an emission intensity as a functionof time of at least one activated material of said combinatorial arrayof materials.
 16. The system of claim 15, further comprising a heatsource capable of selectively heating at least one material of saidcombinatorial array of materials to a predefined temperature.
 17. Thesystem of claim 16, wherein said heat source is selected from the groupconsisting of focussed infrared radiation sources and resistive heatingelements.
 18. The system of claim 15, further comprising: a standardmaterial within said reaction chamber, said standard material within afield of view of said infrared camera; and a processor for calculating atemperature difference between said materials of said combinatorialarray and said standard material.
 19. The system of claim 18, furthercomprising means for varying an environmental condition within saidreaction chamber, wherein said environmental condition is selected fromthe group consisting of chamber temperature, chamber pressure, andchamber gas composition.
 20. A system for monitoring the infraredabsorption of each of a plurality of materials contained on acombinatorial array of materials, comprising: an IR transparentsubstrate containing said combinatorial array of materials; an infraredradiation source, wherein said radiation source sequentially irradiateseach of said plurality of materials; and an infrared detection systemmonitoring material absorption as a function of time for each of saidplurality of materials.
 21. The system of claim 20, wherein saidradiation source is a monochromatic source.
 22. The system of claim 20,wherein said radiation source is a polychromatic source, said systemfurther comprising at least one optical filter interposed between saidcombinatorial array of materials and said infrared detection system. 23.A system for monitoring the infrared absorption of each of a pluralityof materials contained on a combinatorial array of materials,comprising: an IR transparent substrate containing said combinatorialarray of materials; an infrared radiation source, wherein said radiationsource simultaneously irradiates said plurality of materials; and aninfrared detection system monitoring material absorption as a functionof time for each of said plurality of materials.
 24. The system of claim23, wherein said radiation source is a monochromatic source.
 25. Thesystem of claim 23, wherein said radiation source is a polychromaticsource, said system further comprising at least one optical filterinterposed between said combinatorial array of materials and saidinfrared detection system.
 26. A system for simultaneouslycharacterizing a plurality of chemical reactions contained on acombinatorial array of materials, comprising: an IR transparentsubstrate containing said combinatorial array of materials; a modulatedinfrared radiation source, wherein said radiation source simultaneouslyirradiates said combinatorial array of materials; an optical elementinterposed between said combinatorial array of materials and a focalplane array of a high speed infrared camera, wherein said opticalelement focuses radiation from said combinatorial array of materialsonto said focal plane array; and a processor coupled to said infraredcamera, said processor transforming sequential intensity profilescaptured by said camera into infrared spectra using Fourier analysis.27. The system of claim 26, wherein said radiation source is furthercomprised of an interferometer.
 28. The system of claim 27, wherein amirror within said interferometer moves at a constant velocity resultingin a continuous output.
 29. A system for monitoring the infraredemission of each of a plurality of materials contained on acombinatorial array of materials, comprising: a substrate containingsaid combinatorial array of materials; an infrared radiation sourceemitting radiation of at least a first wavelength, wherein saidradiation source irradiates said plurality of materials; and an infrareddetection system monitoring infrared emission of at least a secondwavelength as a function of time for each of said plurality ofmaterials.
 30. A method of characterizing a relative thermal diffusivityfor a plurality of materials, comprising the steps of: providing athermally uniform substrate; synthesizing said plurality of materials ona first surface of said substrate; irradiating a second surface of saidsubstrate with an infrared source; modulating said infrared source; andmonitoring a temperature change associated with each of said pluralityof materials as a function of time, said temperature change indicativeof said relative thermal diffusivity of said plurality of materials. 31.A system for characterizing a relative thermal diffusivity for aplurality of materials, comprising: a thermally uniform substratecontaining said plurality of materials on a first surface of saidsubstrate; a modulated IR radiation source directing modulated IRradiation at a second surface of said substrate, wherein said IRradiation is substantially uniform across at least one material of saidplurality of materials; an IR detector monitoring a temperature changeassociated with said at least one material of said plurality ofmaterials as a function of time, said IR detector outputting a signalcorresponding to a monitored temperature; a translation stage systemcoupled to said substrate and said IR detector, said translation stagerepositioning said substrate and said IR detector so that said IRdetector sequentially monitors said temperature change as a function oftime for each material of said plurality of materials, and wherein eachmaterial of said plurality of materials receives substantiallyequivalent IR radiation from said IR radiation source; and a processorcoupled to said IR detector, wherein said processor records said outputsignals from said detector and determines said relative thermaldiffusivity of said plurality of materials.
 32. A system forcharacterizing a relative thermal diffusivity for a plurality ofmaterials, comprising: a thermally uniform substrate containing saidplurality of materials on a first surface of said substrate; a modulatedIR radiation source directing modulated IR radiation at a second surfaceof said substrate, wherein said IR radiation is substantially uniformacross said plurality of materials; an IR detector array monitoring atemperature change associated with each material of said plurality ofmaterials as a function of time, said IR detector outputting a pluralityof signals corresponding to said monitored temperature change for eachmaterial; and a processor coupled to said IR detector array, whereinsaid processor records said output signals from said detector array anddetermines said relative thermal diffusivity of said plurality ofmaterials.